2014 Sheep Request - Acquisition of a GC/MS/MS Instrument for State-of-the-Art Neurosteroid Quantification

Durham Va Medical Center, Durham NC

Investigators

Abstract

? DESCRIPTION (provided by applicant): Our Durham VA laboratory is fortunate to be one of few laboratories internationally with the capacity to quantify neurosteroids (endogenous molecules enriched in brain) using highly sensitive and specific `gold standard' mass spectrometry-based technologies. This state-of-the-art methodology was optimized and validated in our lab at the Durham VA Medical Center in 2004-2005, and the first peer-reviewed manuscripts utilizing this technology were published in 2006 (please see Appendix for listing, which includes 2 Priority Communications in Biological Psychiatry [impact factor 10.3] and 4 manuscripts in Neuropsychopharmacology [impact factor 7.8]). These publications involved collaborations with multiple VA investigators, both locally and across the country. Early neurosteroid biomarker investigations in rodent models and human postmortem brain tissue have been rapidly translated to proof-of-concept clinical trials testing neurosteroids as pharmacological interventions in Veteran cohorts with schizophrenia, traumatic brain injury, post-traumatic stress disorder, pain conditions, and other CNS disorders. We currently hold 4 FDA Investigational New Drug numbers for these studies, resulting from rapid translation of basic science `bench' efforts to clinical investigations. Also, pending patents related to these technologies focusing on use of neurosteroids and derivatives for the treatment of CNS conditions are co-owned by VA and Duke (208 waiver in place, see Appendix). Our first mass spectrometry instrumentation was purchased in 2001 - an Agilent 5973 gas chromatography/mass spectrometry (GC/MS) instrument that we are currently utilizing for our neurosteroid analytic projects (and with which we have achieved femtomolar sensitivity for neurosteroid quantification). Unfortunately, as of September 2014, Agilent will no longer support this GC/MS instrument with a service contract - because the GC/MS instrument was purchased over 12 years ago, it is considered obsolete from an industry support perspective, and thus Agilent will no longer guarantee repairs, service, or replacement of parts. As a result, current and future VA neurosteroid projects are at risk. Specifically, multiple VA studies and multiple VA investigators depend on this neurosteroid quantification capacity in order to complete the aims of funded VA Merit Review grants and Career Development Awards. Further, continued availability of this valuable technology to VA investigators will be pivotal to leveraging new scientific leads for development of novel therapeutics to treat conditions impacting large numbers of Veterans. It is also essential to have continued mass spectrometry capacity at VA because some high-impact journals are now requiring mass spectrometry approaches - and will no longer publish immunoassay methodologies (as of January 1, 2015 for J Clin Endocrinol Metab; see Appendix). The replacement of the GC/MS instrumentation is thus an urgent and critical scientific need for VA. We therefore request acquisition of a GC/MS/MS instrument in order to: 1.) Replace the current GC/MS instrument, for which we can no longer obtain a service contract and which will soon be rendered unusable secondary to absence of repair support and replacement parts 2.) Improve upon the current GC/MS methodology via acquisition of a GC/MS/MS instrument in order to: a. Further increase methodological sensitivity, as the GC/MS/MS instrument is even more sensitive than our current GC/MS instrument, thus likely requiring less labor-intensive sample preparation; thereby it would b. Increase our overall sample throughput and capacity, making it possible to collaborate with more VA investigators and to meet the ever-increasing demand for this technology (which certain high-impact journals are now also requiring for publication)